Результаты поиска

ERK signaling promotes IKKε expression and oncogenic functions in pancreatic cancer cells in association with TBK1.

A variety of cancers utilize RAS-regulated signaling pathways to promote oncogenic phenotypes. A widely studied example is pancreatic cancer, where mutant KRAS signaling leads to activation of MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase [ERK])-ERK and downstream signaling, which promotes oncogenic mechanisms, including cell proliferation. Importantly, ERK inhibitors have shown efficacy in some cancer clinical trials. Previously, others have studied the effects of the related kinases TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor kappa-B kinase epsi

[First line treatment of non-oncogene-addicted metastatic non-small cell lung cancer].

Since 2017, anti-PD-(L)1 immunotherapy has been the cornerstone of first-line treatment for stage IV non-oncogene-addicted non-small cell lung cancer. Its phase I development has established that the level of PD-L1 expression by tumor cells is predictive of response rate and progression-free survival. Above 50%, it makes chemotherapy not mandatory, with a median survival for pembrolizumab monotherapy of around 26 months and five-year survival of 32%. Large phase III studies have also validated the combination of anti-PD-(L)1 immunotherapy and platinum-based chemotherapy regardless of PD-L1 lev

Reprogramming oncogenic mitochondria in pancreatic adenocarcinoma through BRD4 inhibition leads to programmed cell death.

Pancreatic ductal adenocarcinoma (PDA) is an almost universally fatal disease. Recent advances in the understanding of PDA bioenergetic dynamic equilibrium have illuminated a potential therapeutic target in bromodomain-related protein 4 (BRD4), the most active member of the bromo- and extraterminal domain (BET) protein family of transcription factors. We previously demonstrated that BET inhibitors (BETi) decrease PDA cell proliferation and enhance chemosensitivity. We hypothesized that BETi activates mitophagy and ferroptosis in PDA. Using pharmacological and genetic BRD4 inhibition in PDA pat

MDM2 Knockdown Reduces the Oncogenic Activities and Enhances NIS Protein Abundance in Papillary Thyroid Cancer.

BACKGROUND/AIM: Despite the excellent prognosis post thyroidectomy and radioiodine therapy, papillary thyroid cancer (PTC) patients still un … t, pathway enrichment analysis was conducted to derive candidate genes and pathways involved in PTC oncogenesis and NIS activity. The expression of candidate genes was confirmed by an independent TCGA dataset. Then, we used siRNA to knockdown the MDM2 gene to examine the potential pathogenesis mechanisms of MDM2 and MDM2-P53-NIS axis in cells. Also, we exam …

Phase separation of the oncogenic fusion protein EWS::FLI1 is modulated by its DNA-binding domain.

Ewing sarcoma (EwS) is an aggressive cancer of bone and soft tissue that predominantly affects children and young adults. A chromosomal translocation joins the low-complexity domain (LCD) of the RNA-binding protein EWS (EWSLCD) with the DNA-binding domain of Friend leukemia integration 1 (FLI1DBD), creating EWS::FLI1, a potent fusion oncoprotein essential for EwS development and responsible for over 85% of EwS tumors. EWS::FLI1 forms biomolecular condensates in vivo and promotes tumorigenesis through mediation of aberrant transcriptional changes and by interfering with the normal functions of

Deciphering and targeting oncogenic pathways through integrated approaches and amino acid metabolism in hematologic malignancies.

Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, represent a diverse group of blood cancers driven by complex oncogenic pathways and genetic aberrations. Despite advances in treatment, resistance and relapse remain significant clinical challenges. This review presents an integrative approach to blood cancer therapy, highlighting the convergence of precision medicine, CRISPR-based gene editing, immunotherapy (including CAR-T cells and immune checkpoint inhibitors), and targeted modulation of amino acid metabolism. We investigate the molecular pathways driving tumour

Совпадение в полном тексте источника
… Conversely, in some blood malignancies, global hypomethylation activates oncogenes and induces genomic instability. … CRISPR-based genome editing has enhanced the precision of manipulating oncogenic drivers in this pathway. …

Inhibition of the PI3K/AKT signaling pathway blocks the oncogenic activity of TRIM26 in prostate cancer cells.

The tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase with strong oncogenic activity in various cancers. However, its role and molecular mechanism in prostate cancer (PCa) remain elusive. To clarify its role in promoting PCa progression, we evaluated TRIM26 expression in cells and clinical specimens using immunohistochemistry and found that TRIM26 was significantly upregulated in PCa tissue. Moreover, high TRIM26 levels predicted a poor prognosis in patients with PCa. Ectopic overexpression of TRIM26 increased PCa cell proliferation and migration, and this activity was

Germline mutation in Cbl proto-oncogene B is associated with inherited thrombocytopenia and predisposes megakaryocytes to ferroptosis.

BACKGROUND: Inherited thrombocytopenias (ITs) are a group of heterogeneous diseases characterized by low platelet counts and bleeding diathesis. ITs are primarily caused by mutations in genes involved in megakaryocyte differentiation, maturation and platelet release. To date, ITs encompass 45 disorders with different degrees of variability in the prognosis. OBJECTIVES: We aimed to identify the predisposing gene in members of a family with inherited thrombocytopenia and elucidate its etiology and pathogenesis. METHODS: Whole exome sequencing was performed using samples from the proband and th

Exploring the oncogenic roles of T-box transcription factor TBX2 and its potential as a therapeutic target.

During embryonic development, the T-box transcription factor TBX2 regulates key processes such as cell fate decisions, migration and tissue morphogenesis, and mutations that lead to reduced TBX2 levels result in developmental abnormalities including congenital heart and skeletal defects. TBX2, on the other hand, is overexpressed in a plethora of cancers where it functions as a powerful oncogene contributing to processes ranging from the bypass of senescence and cell death pathways to the promotion of cell proliferation, and epithelial-to-mesenchymal transition to drive invasion and metastasis.

Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.

Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities lin

Oncogenic stress alters predator-prey interactions between a globally invasive and a native planaria species.

Oncogenic pressures, factors that increase tumor risk, are intensifying with human-driven environmental change, yet their ecological effects remain mainly unquantified. We examined how UVB-induced oncogenic stress affects interactions between two Australian freshwater planaria: the globally invasive predator Girardia tigrina and the native prey Cura pinguis. We hypothesized that DNA damage could either heighten prey vulnerability or impair predator performance. Native planaria showed less UVB-induced DNA damage, likely due to darker pigmentation, while damage in G. tigrina reduced predation ra

Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor-ligand interactions.

Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. Characteristic alterations of the chromosome 19 microRNA cluster (C19MC) are observed in most ETMR; however, the ramifications of C19MC activation and the complex cellular architecture of ETMR remain understudied. Here we analyze 11 ETMR samples from patients using single-cell transcriptomics and multiplexed spatial imaging. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly ex

Impaired MC3T3-E1 osteoblast differentiation triggered by oncogenic HRAS is rescued by the farnesyltransferase inhibitor Tipifarnib.

HRAS is a ubiquitously expressed protein and functions as a central regulator of cellular homeostasis. In somatic cells, mutations in this gene cause cancer, while germline mutations trigger a developmental disorder known as Costello syndrome (CS). Among numerous pathologies, adult CS patients develop osteoporosis. Previous studies revealed that HRAS is implicated in bone homeostasis by controlling osteoblast differentiation, adaptation to mechanical strain and repression of RANKL expression in mature osteoblasts, and by regulating osteoclast differentiation. However, the impact of HRAS on ost

PALB2 mutations increase oncogenic properties of breast epithelial cells by enhancing JAM3 and PARVB expression.

High-risk genes, heterozygous pathogenic mutations of which predispose to familial breast cancers, typically encode factors securing a proper DNA damage response. PALB2 is one such major cellular factor that is needed for alleviation of genomic, replicative, and oxidative stresses. Thus, it has a crucial role in maintaining genomic integrity and protecting cells against cancer. While the malfunctions in DNA damage repair of PALB2-mutated cells have extensively been documented, our research continues to explore cells' other pro-tumorigenic characteristics, focusing particularly on the early sta

Human T-cell leukemia virus type 1: oncogenic potential and vaccine development strategies.

The human T-cell lymphotropic virus type 1 (HTLV-1) is a highly oncogenic retrovirus recognized as the causative agent of adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Among the key risk factors for ATLL development are high proviral load, reduced anti-Tax immune responses, and elevated levels of soluble interleukin-2 receptor. Unlike classical oncogenic viruses, HTLV-1 does not encode proto-oncogenes but instead drives cellular transformation through a combination of mechanisms, including viral gene dysregulation, chromatin remo…

HBV sequence integrated to enhancer acting as oncogenic driver epigenetically promotes hepatocellular carcinoma development.

BACKGROUND: HBV integration is considered as the main contributor to hepatocellular carcinoma (HCC). However, whether HBV integrated sequences determine genotype pathogenicity and how to block their function during HCC progression remains unclear. METHODS: An in vitro HBV-infected PHH model and liver cancer cell lines were established to confirm the pathogenic potential of HBV-SITEs. The roles of HBV-SITE-1 in HCC development were analyzed using cellular phenotypic assays and molecular biology techniques, including the combined analysis of RNA-seq and ChIP-seq. Animal models were also used to

Is malathion oncogenic for mosquitoes? A transcriptomic and histological study of adults derived from malathion exposed larvae.

Malathion is a widely used pesticide with potentially oncogenic properties and may have deleterious effects on organism health and fitness. Although malathion use is now restricted in the European Union, it remains widely used for public health campaigns in other parts of the world, particularly for mosquito control. Understanding its sublethal and long-term effects is thus essential, both for evaluating its ecotoxicological impacts and for anticipating resistance mechanisms. However, empiric data on its effects in wild organisms - especially in invertebrates - remain limited. Here, we quantit

Concordance in Oncogenic Alterations Between the Primary Tumor and Advanced Disease: Insights Into the Heterogeneity of Intrahepatic Cholangiocarcinoma.

PURPOSE: Intrahepatic cholangiocarcinoma (ICCA) is characterized by significant phenotypic and clinical heterogeneities and poor response to systemic therapy, potentially related to underlying heterogeneity in oncogenic alterations. We aimed to characterize the genomic heterogeneity between primary tumors and advanced disease in patients with ICCA. METHODS: Biopsy-proven CCA specimens (primary tumor and paired advanced disease [metastatic disease, progressive disease on systemic therapy, or postoperative recurrence]) from two institutions were subjected to targeted next-generation sequencing.

RBM10 C761Y mutation induced oncogenic ASPM isoforms and regulated β-catenin signaling in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary tract cancer. Our previous CCA mutation pattern study focused on genes in the post-transcription modification process, among which the alternative splicing factor RBM10 captured our attention. However, the roles of RBM10 wild type and mutations in CCA remain unclear. METHODS: RBM10 mutation spectrum in CCA was clarified using our initial data and other CCA genomic datasets from domestic and international sources. Real-time PCR and tissue microarray were used to detect RBM10 clinical association. Function assays we